Field of the Invention
The invention relates to novel specific immunophilin ligands of the formula ##STR2##
The radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, Y, A, B and D are defined as follows:
R.sub.1 is hydrogen, a (C.sub.1 -C.sub.12)-alkyl group or a (C.sub.2 -C.sub.6)-alkoxy group, where the alkyl group is linear or branched and can be substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S or O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazines, thiophene, furan or imidazole, or monosubstituted or polysubstituted by a phenyl ring. This phenyl ring can itself be monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl. PA1 R.sub.1 can also be the amine radical of the methyl esters of the following amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecolic acid, piperidine-4-carboxylic acid, piperidine-3-carboxylic acid, .epsilon.-NH.sub.2 -lysine, .epsilon.-Z-NH-lysine, .epsilon.-(2Cl-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Tos), asparagine, citrulline, homocitrulline, ornithine, proline, indoline-2-carboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid and 8-aminooctanoic acid. PA1 R.sub.2 is hydrogen, a (C.sub.1 -C.sub.12)-alkyl group or a (C.sub.2 -C.sub.6)-alkoxy group, where the alkyl group is linear or branched and can be substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S or O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazines, thiophene, furan or imidazole, or monosubstituted or polysubstituted by a phenyl ring. This phenyl ring can itself be monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl. PA1 R.sub.3 is hydrogen, butoxycarbonyl, carboxybenzyl, mono-, bi- or tri-cyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, preferably N, S or O, where aryl or heteroaryl itself can be monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl. R.sub.3 can also be; carboxy-(C.sub.1 -C.sub.6)-alkyl, where the alkyl group can be linear or branched and can be substituted by a monocyclic or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S or O, such as morpholine, piperazine, piperidine, indole, indazole, phthalazines, thiophene, furan or imidazole, or monosubstituted or polysubstituted by a phenyl ring, where this phenyl ring itself can be monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl., carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl. PA1 R.sub.3 can also be the acid radical of the following amino acids: histidine, leucine, valine, serine (Bzl), threonine, pipecolic acid, piperidine-4-carboxylic acid, piperidine-3-carboxylic acid, .epsilon.-NH.sub.2 -lysine, .epsilon.-Z-NH-lysine, .epsilon.-(2Cl-Z)-NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Tos), asparagine, citrulline, homocitrulline, ornithine, proline, indoline-2-carboxylic acid, octahydroindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid and 8-aminooctanoic acid, where the N terminus of the amino acids can be substituted by butoxycarbonyl, carboxybenzyl or the acid radical of mono-, bi- or tri-cyclic arylcarboxylic or heteroarylcarboxylic acids having 1-4 heteroatoms, preferably N, S or O, such as methoxyphenylacetic acid, naphthylacetic acid, pyridylacetic acid, quinazolinonylacetic acid, indazolylacetic acid, indolylglyoxylic acid, phenylglyoxylic acid, isobutylglyoxylic acid and 2-aminothiazole-4-glyoxylic acid, or by carboxy-(C.sub.1 -C.sub.12)-alkyl, carboxycyclopentane, carboxycyclohexane or benzoyl, which can be monosubstituted or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups or carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols. PA1 R.sub.4 is H, F or OR.sub.5. PA1 R.sub.5 is hydrogen, (C.sub.3 -C.sub.7)-cycloalkyl, (C.sub.1 -C.sub.6)-alkyl or carboxy-(C.sub.1 -C.sub.6)-alkyl, where the alkyl group can be linear or branched and can be substituted by a mono-, bi- or tri-cyclic carbonylaryl or carbonylheteroaryl having 1-4 heteroatoms, preferably N, S or O, where aryl or heteroaryl itself can be monosubstituted or polysubstituted by halogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with linear or branched (C.sub.1 -C.sub.6)-alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups or amino groups, which in turn are substituted by benzyl, benzoyl or acetyl. PA1 A is aromatic, non-aromatic, aromatic/heterocyclic having 1-2 heteroatoms, preferably N, S or O, or non-aromatic/heterocyclic having 1-2 heteroatoms, preferably N, S or O. PA1 B is CH.sub.2. PA1 D is CH. PA1 B--D is CH.dbd.C. PA1 X is O, S or H.sub.2. PA1 Y is C or a single bond.
The invention further relates to the biocompatible salts of the compounds of the formula I, to the processes for the preparation of the compounds of the formula I and to their use in pharmaceutics.
2. Background Information
Cyclosporin A (CsA) and FK 506 are immunosuppressive natural substances derived from fungi, which inhibit the Ca.sup.2+ -dependent signal transmission pathway in some types of cells. In T cells both agents inhibit the transcription of a number of genes, including the IL-2 gene, which is activated by stimulation of the T cell receptors (TCR). FK 506 and CsA both bind with high affinity to soluble receptor proteins (G. Fischer et al., Nature 337, 476-478, 1989; M. W. Harding et al., Nature 341, 755-760, 1989). The FK 506 receptor and the CsA receptor have been called FKBP and cyclophilin (Cyp) respectively. Both proteins catalyse the isomerization of cis and trans amide bond rotamers of peptides and are also frequently called immunophilins.
The CsA-Cyp or FK 506-FKBP supermolecule binds calcineurin (CN) and inhibits its phosphatase activity. The cytosolic phosphorylated component of the transcription factor NF-AT has been recognized as a cellular target molecule of CN; if the CN activity is absent, said molecule cannot be dephosphorylated for action in the cell nucleus, so the active transcription complex on the IL-2 promoter cannot be switched on (M. K. Rosen, S. L. Schreiber, Angew. Chem. 104 (1992), 413-430; G. Fischer, Angew. Chem. 106 (1994), 1479-1501).
Allergic asthmatic diseases arise from an inflammatory reaction controlled by T cells and their mediators. Corticosteroids are still the preferred drugs in the treatment of many allergic diseases. CsA and FK 506 have also proved to be favourable therapeutic agents for bronchial asthma and underlying inflammations, in both animal experiments and clinical studies. In animal experiments it has been possible to demonstrate the blocking of various cytokines, like IL-2, IL-4 and IL-5, which cause allergy-induced inflammations.
Despite the numerous attempts to identify new active immunophilin inhibitors, it has hitherto been impossible to prepare or isolate more active structures than CsA, FK 506, rapamycin or derivatives of these natural substances. However, the high inhibitory potential of CsA, FK 506 and rapamycin is very considerably reduced by the manifold side effects, especially on the kidneys, and neurotoxicity (N. H. Sigal et al., J. Exp. Med. 173, 619-628, 1991). The background to this fact is the non-specificity of the interaction between immunophilin ligands and the cell-specific binding proteins. It is this which substantially restricts the known medicinal-therapeutic action of these immunosuppressants. The absence of selectivity of the compounds proves to be a further problem, especially in long-term therapy.